Stereoselective syntheses of peptide analogues 1-4 will be performed to investigate enzyme-substrate interactions for HIV-1 protease. "Norpeptides" 1 contain dipeptide surrogates wherein the amide bond has been completely deleted, and mimic an HIV-1 protease substrate known to cleave at that particular linkage. Lactams 2 and 3 are designed to explore the stereochemical constraints which favor binding of a substrate to an enzyme. Similarly, stereoisomers of 4 are designed to project substituents in a defined orientation to explore hydrophobic binding pockets in the enzyme, but this substrate also has hydroxyl functionality to resemble tetrahedral intermediates in hydrolysates. Structures of these peptidomimetics in solution (NMR and computational studies) and in the solid state (X-ray) will be correlated with their Ki values. The immediate objective of this work is to use conformationally restrained molecules to explore the fit of substrates into HIV-1 protease, but if any of these substrates are shown to be particularly good inhibitors this will provide leads for design of non-peptide molecules with potential anti-HIV activity in vivo.